This project will examine the use of a three component pre-targeting radioimmunotherapy (PRIT) strategy in breast cancer animal models and patients with metastatic breast cancer. The three components include a novel recombinant fusion protein composed of four single chain antibodies and streptavidin (sFv4/SA) which will target breast cancer tumor-associated antigens (TAG-72 and MUC-1). The second component is a synthetic clearing agent which produces rapid hepatic clearance of circulating sFv4/SA prior to administration of the third component, Biotin-DOTA-isotope carrying imaging and therapeutic isotopes. The isotope delivery system as a low m.w. (0.9 kD) with rapid distribution throughout the body for tumor localization and rapid urinary excretion. This strategy has a 10-fld increase in tumor to normal tissue ratios as compared to radiolabeled antibodies. We will carry out a series of studies in breast cancer animal models to optimize therapy variables, explore several therapeutic isotopes and examine therapeutic efficacy and several sites of metastases. Human trials will include phase I and II trials of CC49 sFv4/SA followed by Biotin-DOTA-111In/90Y as well as subsequent trials derived from the animal model studies. These studies are to be done in collaboration with NeoRx, Inc.